7. PROJECT SUMMARY / ABSTRACT Rheumatoid arthritis (RA) is the most common autoimmune inflammatory disease, characterized by persistent synovitis and systemic inflammation. RA is generally considered as a multifactorial disease, caused by both genetic factors and environmental exposures. Although some individual dietary factors have been identified to be associated with the development of RA, few studies have examined the effects of overall dietary quality and dietary patterns on RA risk. In our previous studies, we have demonstrated that adherence to the Dietary Guidelines for Americans or following a Prudent dietary pattern is associated with reduced RA risk, while a Western dietary pattern or a dietary inflammatory pattern, characterized by high intakes of red and processed meats, refined grains, desserts and sweets, and high-fat dairy products, increases RA risk in young and middle-aged women. However, little is known about whether modifying dietary quality influences subsequent RA risk. Often, it is not ethically or practically possible to conduct a perfectly randomized trial to study diet and risk of rare diseases, instead large longitudinal studies with repeated dietary measures can provide unique opportunities to evaluate the effect of diet changes on RA risk reduction using advanced causal inference models, which will have direct relevance for populations at highest risk such as first degree relatives of RA patients. Dietary factors directly and indirectly play an important role in the genesis of obesity. Individuals with obesity are at increased risk of major chronic diseases. We also identified obesity as a significant risk factor of RA, although the biologic mechanism is not yet understood. Further study is needed to evaluate the influences of weight gain or weight loss on the risk of RA using causal models. The adipokines produced by the adipose tissue, leading to a chronic inflammatory state, may play a central role in the development of obesity-related complications. In this application we propose to evaluate the modification of dietary quality as a potential strategy to prevent future development of RA using well-established causal inference models: Marginal Structural Models. This study also extends our earlier work to examine the influences of weight changes and body fat distribution on RA risk. We will also examine whether circulating adipokines associated with an increased risk of developing RA, and mediate the observed associations of dietary quality and obesity with RA risk in a matched case-control study nested in NHS and NHS II cohorts.